Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease (PD), Huntington's disease, amyotrophic lateral sclerosis and prion diseases are debilitating diseases which affect cognition and/or muscle control. These diseases are a subset of protein misfolding diseases. Protein folding is an essential process for protein function in all organisms, and conditions that disrupt protein folding present a threat to cell viability. In some cases, the disease arises because a specific protein is no longer functional when adopting a misfolded state. In other diseases, the pathological state originates because misfolding occurs concomitantly with aggregation, and the underlying aggregates are detrimental.
Even though neurodegenerative diseases such as Alzheimer's and Parkinson's are caused by different proteins, both involve the accumulation of insoluble fibrous protein deposits, called amyloids. For example, Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), which are collectively referred to as “synucleinopathies,” have been linked to the accumulation of aggregated forms of the α-synuclein protein in neurons in the brain. As the primary neuropathologic change of PD, the degeneration of dopaminergic neurons occurs in the substantia nigra, as well as Lewy bodies (LB) and Lewy neurites (LN). To date, the pathogenic mechanism of PD has not been fully discovered.
α-Synuclein is a presynaptic terminal protein that consists of 140-amino acid protein that plays an important function in the central nervous system including synaptic vesicle recycling and synthesis, vesicular storage, and neurotransmitter release. It is specifically upregulated in a discrete population of presynaptic terminals of the brain during acquisition-related synaptic rearrangement. α-Synuclein naturally exists in a highly soluble, unfolded state. Evidence suggests that filamentous aggregates of α-synuclein accumulate at the pre-synaptic membrane and trigger synapse dysfunction and neuronal cell death in synucleinopathies, and may be the cause of Parkinson's and DLB. α-Synuclein aggregation has been identified by antibody-immunohistological studies as the major component of Lewy bodies, which are microscopic protein deposits in deteriorating nerve cells. Accumulation of misfolded, fibrillar α-synuclein in Lewy bodies (LB) and Lewy neurites (LN) is considered a hallmark of PD.
The diagnosis of PD is mainly based on the clinical symptoms such as rest tremor, bradykinesia, and rigidity. The current treatment for PD is to slow the disease progression and minimize the disease symptoms in the patients. Therefore, a method of diagnosing PD in the very early stage can greatly help the physicians to design the therapy accordingly, and to slow the disease progression.
There remains a need for improved diagnostic methods for identifying aggregations of misfolded proteins, including α-synuclein for early detection and ongoing monitoring of PD in subjects.